A 25-year-old banker, a nonsmoker and non- drinker, presented with pain in the hands and feet for 4 weeks that progressed to involve shoulders and hips. Pain was associated with constipation, followed by diarrhea. He had no prior trauma, vaccinations, or infectious symptoms. Medical history was noncontributory; he was on no medication. He had consulted numerous doctors for the pain, who noted transient urinary hesitancy, tachycardia, and hypertension that required short duration treatment with antihypertensives. All symptoms except the pain resolved spontaneously. On examination, he was afebrile, alert, and oriented. Cranial nerves were intact; there was no ptosis, diplopia, or facial plegia. Four-limb power was Medical Research Council 5/5 proximally and 4/5 distally, limited by pain. Reflexes were just elicitable; anal tone was intact. Cerebellar signs were absent. Gait was slow from bilateral sole pain. No joint deformities or skin abnormalities were seen. He often adopted a posture with both arms abducted and fingers extended, which alleviated pain. Sensory testing revealed hyperalgesia and brush allodynia over the hands and feet. Temperature, vibration, and proprioception were preserved.
患者，25岁银行家，双侧手、脚疼痛4周，逐渐进展，累及双肩及臀部。否认吸烟饮酒史。疼痛时伴便秘，后出现腹泻。既往史无殊，否认外伤、感染史，否认疫苗接种史；否认药物应用史。患者因疼痛曾多处就诊，医生注意到其有短暂排尿不畅、心动过速及高血压，并给予其短时间降压治疗。除疼痛外所有症状自行缓解。体检示，患者体温、意识及定向力正常。颅神经正常；无眼睑下垂、复视及面瘫。四肢肌力因疼痛受限，远端4级，近端5级。反射仅可引出；肛门张力正常。无小脑受损体征。因双侧足底疼痛而步态缓慢。无关节畸形及皮肤异常。患者经常采用双臂交叉、手指伸直的姿势以减轻疼痛。感觉检查示双侧手、脚存在痛觉过敏及毛刷刺激诱发性疼痛 。温度觉、振动觉及本体感觉正常。
Questions for consideration
1. What differential diagnoses would you consider?
2. What investigations would you perform to con-firm the diagnosis?
问题思考
1. 如何考虑鉴别诊断？
2. 应做何检查以确诊？
Hyporeflexia and glove stocking sensory disturbance strongly suggest a length-dependent polyneuropathy. Allodynia and pain in the distal extremities in the absence of vibration, proprioception, and touch involvement point toward involvement of the nociceptive small sensory fibers, sparing large sensory fibers.
反射减退和手套-袜子样感觉障碍强烈提示长度依赖性多神经病。无触觉、振动觉及本体感觉异常的远端肢体异常性疼痛提示参与疼痛的小感觉纤维受累，大感觉纤维正常。
Question for consideration
1. What preliminary investigations would you consider?
问题思考
1. 应做何初步检查？
The most apparent abnormality in the blood tests was hyponatremia. The syndrome of inappropriate antidiuretic hormone (SIADH) is diagnosed when urine osmolality and sodium are high in the presence of low serum osmolality and hyponatremia. In view of the subacute onset of dysesthesia and pain, hyporeflexia, and SIADH, a sensory variant of Guillain-Barré syndrome (GBS) should be considered.
患者血液检查最明显的问题是低钠血症。当尿钠、尿渗透压升高而血钠、血清渗透压降低时应考虑抗利尿激素分泌异常综合征（SIADH)的诊断。鉴于患者亚急性发作的触刺激痛、反射减退及SIADH，应考虑吉兰-巴雷综合征（GBS）感觉变异型的诊断。
Workup for other causes of subacute polyneuropathy included normal values for vitamin B12, fasting glucose, and thyroid function, making nutritional and metabolic disorders improbable. Normal erythrocyte sedimentation rate (ESR), normal C-reactive protein, and absence of specific autoantibodies render autoimmune causes from systemic lupus erythematosus or Sj?gren syndrome unlikely. Thorough history and a normal toxicology screen excluded neurotoxins such as metronidazole and solvents, which can cause small fiber neuropathy. Infectious causes from HIV and hepatitis B and C were excluded with negative serum antibodies and negative hepatitis B surface antigen. Additionally, in parts of the world where Lyme disease is endemic, serologic testing for Borrelia burgdorferi, an infectious cause of peripheral neuropathy, should be performed. A small proportion of sarcoidosis patients have associated peripheral neuropathy, and in populations where sarcoidosis is common, chest X-ray is performed to look for hilar adenopathy or parenchymal changes consistent with pulmonary sarcoidosis, and serum angiotensin converting enzyme levels checked. Chronic drinkers are prone to developing thiamine deficiency, which may present as a small fiber neuropathy, necessitating serum vitamin B1 level assessment. For patients of ethnicities where celiac disease is common (North European and Australasian populations), antigliadin antibodies should be worked up.
可引起亚急性多神经病的其他病因相关的检查如维生素B12、空腹血糖和甲状腺功能正常，提示营养和代谢性疾病的可能性不大。血沉(ESR)、C反应蛋白正常及特定自体抗体阴性可排除系统性红斑狼疮或干燥综合征引起多发性神经病的可能。毒物接触史和毒理学检查正常可排除甲硝唑和有机溶剂等神经毒素导致小纤维神经病的可能。HIV、乙肝、丙肝病毒抗体阴性及乙肝表面抗原阴性排除了这些病毒感染导致本病的可能。此外，在莱姆病流行地区，伯氏疏螺旋体感染可引起周围神经病，应对患者进行相关血清学检测。一小部分结节病患者可出现周围神经病变；因此，在结节病高发人群中，应用血清血管紧张素转换酶水平检测及胸部X线摄影寻找符合肺结节病的肺门腺病或肺实质病变。长期饮酒易导致硫胺素缺乏，可表现为小纤维神经病,需要测定血清维生素B1水平。对于来自乳糜泻高发种族(北欧和澳大拉西亚人)的患者，应检查抗麦胶蛋白抗体。
Chest X-ray and CT of the thorax, abdomen, and pelvis were performed to exclude occult malignancies as a cause of paraneoplastic neuropathy, which all had normal results. Small-cell lung cancer is the commonest malignancy that can lead to sensory neuropathy, mainly of the large fiber type. Other associated neoplasias are multiple myeloma, monoclonal gammopathies, and lymphomas. Normal ESR, lactate dehydrogenase, and hematologic profile exclude these.
为排除隐匿恶性肿瘤引起的多神经病变，对该患者进行了胸部X光片和胸腹部及骨盆CT检查，结果均正常。小细胞肺癌是最常见的可导致感觉神经病的恶性肿瘤，主要为大纤维受累。其他相关的肿瘤有多发性骨髓瘤、单克隆丙种球蛋白病和淋巴瘤。该患者ESR、乳酸脱氢酶及血液学检查正常排除了上述肿瘤。
Contrasted MRI spine, brain, and brainstem to look for inflammatory and demyelinating lesions had normal results. Enlarged nerve roots, such as can occur in chronic sensory ganglionopathies ，were absent.
脊柱、脑和脑干增强磁共振检查结果正常，未发现炎性及脱髓鞘病变；亦未发现可引起慢性感觉神经节病的神经根增粗。
Question for consideration
1. What further investigations would you consider?
问题思考
1. 应做何进一步检查？
To define the type of polyneuropathy, nerve conduction studies (NCS) of all 4 limbs were ordered and had normal results.
为确定多神经病的类型，对患者进行四肢神经传导检查(NCS)，结果正常。
Lumbar puncture showed normal opening pressure with a CSF leukocyte count of 5/mL, erythrocyte count of 789/mL, glucose 3.3 mmol/L (reference range [RR] 2.2–3.9 mmol/L), and protein of 2.3 g/L (RR 0.1–0.4 g/L). Gram stain and cytology were normal, further excluding infections. Despite a traumatic tap, the patient’s CSF studies showed albuminocytologic dissociation, which often occurs in inflammatory neuropathies, malignancies, or leptomeningeal metastases. The latter 2 are unlikely in view of normal imaging and CSF cytology.
腰椎穿刺检查示脑脊液初压正常，白细胞计数5个/毫升，红细胞计数789个/毫升，葡萄糖3.3mmol/L(参考范围(RR)2.2-3.9mmol/ L)，蛋白质2.3g/L(RR0.1-0.4g/L)。革兰氏染色和细胞学检查正常，进一步排除了感染可能。尽管存在穿刺损伤，患者CSF检查仍显示蛋白-细胞分离。这常见于炎症性神经病，恶性肿瘤或软脑膜转移。鉴于影像学及CSF细胞学检查正常，可基本排除后两者。
Subacute glove and stocking sensory impairment with allodynia, hyporeflexia, and autonomic involvement in combination with normal NCS findings is strongly suggestive of a small fiber neuropathy. The presence of SIADH and albuminocytologic dissociation makes GBS the likely cause. SIADH and albuminocytologic dissociation occur in 50% and 80% of all patients with GBS, respectively.
亚急性手套-袜子样感觉障碍和异常性疼痛、反射减退、自主神经受累，结合神经传导检查结果正常强烈提示小纤维神经病。SIADH和蛋白-细胞分离提示GBS为本病可能的原因。SIADH和蛋白-细胞分离出现在所有GBS患者中的比例分别为50%和80%。
Antiganglioside antibodies (anti-GM1, anti-GQ1b, anti-GD1a, anti-GD1b, and anti-GT1a) were negative, but the sensitivity and specificity of autoantibodies in small fiber GBS is unknown. In the first days of GBS, NCS may be normal. Initial changes include delayed, absent, or impersistent F and H reflexes, a result of proximal nerve root demyelination. In the first to second week, sural sparing occurs with the demyelinating form. With subsequent segmental demyelination, motor studies show prolonged distal latencies, conduction block, and temporal dispersion. Half of the patients will have changes by 2 weeks, and most by 3 weeks. Our patient presented 4 weeks after the onset of symptoms, a time by which changes in NCS should be detectable. Repeated NCS throughout the illness had normal results. A limitation of NCS is that it can not detect damage to small nerve fibers, which were predominantly affected in this patient.
此例患者抗神经节苷抗体(抗-GM1、抗-GQ1b、抗-GD1a、抗-GD1b和抗-GT1a)阴性，但自身抗体对于小纤维型GBS诊断的敏感度和特异度未知。GBS发病第一天，神经传导检查可以是正常的。最初的改变包括近端神经根脱髓鞘引起的F波和H反射潜伏期延长、消失或呈非持续性。在第一至二周，脱髓鞘形式腓肠神经早期暂时豁免。随着节段性脱髓鞘的进一步发生，运动神经传导检测显示远端潜伏期延长、传导阻滞和波形离散。半数患者在经2周时出现改变，大多数患者在经3周时出现。此例患者在症状出现后4周就诊，此时应能检测到其神经传导改变。病程中患者多次进行神经传导检查，结果均正常。神经传导检查的一个缺点是其不能检测小纤维的损伤，这严重影响了此例患者的诊断。
Question for consideration
1. What further investigations can be done to help confirm the diagnosis of small fiber/autonomic involvement?
问题思考
1. 应做何进一步检查以确定小纤维/自主神经受累的诊断？
Skin biopsy was performed and stained for protein gene product 9.5, which showed absence of intraepidermal nerve fibers, consistent with a small fiber neuropathy.
对该患者进行皮肤活检及蛋白基因产物9.5染色，显示表皮内神经纤维缺失，符合小纤维神经病的改变。
Although unstable blood pressure and heart rate and enteric symptoms had resolved prior to admission, we attempted to further investigate for limb sympathetic involvement. Stimulated skin wrinkling test with EMLA had normal results.
虽然患者血压和心率的不稳定及肠道症状在入院前已缓解，我们仍试图针对其肢体交感神经受累进一步检查。采用EMLA进行刺激皮肤皱缩试验结果正常。
The patient was treated with IV immunoglobulin (IVIg) 2 G/kg over 5 days and symptomatically with gabapentin. At follow-up 6 weeks later, symptoms, as assessed by the Visual Analogue Scale pain scale, had improved by more than 80%.
对该患者应用静注免疫球蛋白（IVIg）2G/kg治疗5天以上，并应用加巴喷丁对症治疗。6周后随访，通过视觉模拟疼痛量表评估的症状改善了80％以上。
图 小纤维神经病病因鉴别检查流程图
This case illustrates an approach to acute-onset small fiber neuropathy (figure). Small fibers are unmyelinated C fibers, which are involved in thermal perception, nociception, and a number of autonomic and enteric functions. Hence in patients with small fiber neuropathies, in addition to presenting with burning dysesthesias or pain, which may be spontaneous or sensory induced, they may also present with autonomic and enteric features of constipation, diarrhea, urinary frequency, blood pressure changes, and postural dizziness.
本例阐述了急性发作的小纤维神经病的诊断思路(图)。小纤维为无髓鞘的C类纤维，参与热感知、伤害感受和部分自主神经及肠道功能。因此小纤维神经病变患者，除了自发或感觉刺激诱导的燃烧样感觉障碍或疼痛,他们也可能表现为便秘、腹泻、尿频、血压改变和姿势性头晕等自主神经和肠道功能紊乱。
Multiple diagnostic tests are available to confirm the diagnosis of small fiber neuropathies. Skin biopsy with estimation of intraepidermal nerve fiber density is a commonly accepted gold standard in the diagnosis of small fiber neuropathies and has a high sensitivity (80%). The skin wrinkling test is simple with reasonable sensitivity (up to 80%)
多项诊断试验可用于小纤维神经病的确诊。皮肤活检表皮内神经纤维密度评估是一个已被普遍接受的诊断小纤维神经病的金标准，灵敏度较高(80%)。皮肤皱缩试验较为简单，合理敏感度高达80%。
However, it only tests the sympathetic portion of small fiber neuropathy and in this case there were no clinical clues suggesting persistent sympathetic involvement.
然而，它只能检测小纤维神经病的交感神经部分，此例患者并无临床线索表明存在持续的交感神经受累。
Other tests include quantitative sensory testing, which assesses psychophysical thresholds for cold and warm sensations with a diagnostic efficiency of around 50%. Sympathetic skin response is commonly used to diagnose small fiber neuropathy but has varying sensitivity and reproducibility due to complex central and peripheral pathways. Quantitative sudomotor axon reflex test is an alternative diagnostic tool but test and pretest reliability have been found to be moderate. Finally, microneurography is an invasive test, which by placing recording microelectrodes within nerve fascicles, enables multiple small fibers to be recorded simultaneously.
其他试验包括评估冷温觉心理物理阈值的定量感觉神经检查，诊断效率约为50%。交感皮肤反应常用于诊断小纤维神经病，但由于复杂的中枢及外周通路其灵敏度和重复性波动较大。定量促汗神经轴索反射试验是另一种诊断工具，但试验及验前可靠性不高。此外，微神经造影术是一种侵入性试验，通过将记录微电极放置在神经束内，可同时记录多个小纤维。
The diagnosis of the underlying cause of subacute monophasic small fiber neuropathy depends on the identification of likely underlying causes. When appropriate testing fails to identify the possible etiologies, an autoimmune cause similar to GBS can be considered. A recent approach for GBS diagnosis is the Brighton Criteria, which stratifies patients into 4 levels of diagnostic accuracy, depending on core clinical symptoms and signs of bilateral and flaccid limb weakness, a monophasic course and time between onset and nadir (12 hours–28 days), and decreased or absent deep tendon reflexes, in the absence of any alternative diagnosis for weakness. CSF, neurophysiology, and autoantibodies are supportive.
亚急性单相小纤维神经病的诊断取决于对其可能的潜在病因的识别。当合适的诊断试验未能发现其可能的病因，可以考虑类似于GBS的自身免疫性病因。最近对GBS的诊断方法是布莱顿标准，根据其核心临床症状和双侧弛缓性肢体无力的体征,单相病程和发病达高峰的时间(12小时-28天)，腱反射减弱或消失，无肢体无力的其他替代诊断，将这些患者按诊断准确性分为4个水平。CSF、神经生理学和自身抗体检查支持诊断。
Most diagnostic criteria for GBS emphasize the motor nerves and criteria for sensory GBS are less readily established. Small-fiber GBS, which is also known as a form of sensory GBS, is a controversial diagnosis, but needs consideration where weakness is minimal and nerve conduction tests are normal, in the presence of monophasic signs and symptoms of small fiber involvement.
大多数GBS的诊断标准强调运动神经受累，感觉型GBS的诊断标准则不太容易建立。小纤维型GBS，又为感觉型GBS的一种形式，是一个有争议的诊断。但当存在单相的小纤维受累的症状、体征，而肢体无力不明显且神经传导检查结果正常时需要考虑此诊断。
Saifudheen et al found that 48% of patients with GBS had associated SIADH, which was also found to be a poor prognostic predictor. The pathogenesis of SIADH in GBS has not been fully understood but has been postulated to be due to osmotic resetting and enhanced renal tubular sensitivity to antidiuretic hormone.
Saifudheen等发现48%的GBS患者同时合并SIADH，后者也是GBS预后不良的指标之一。GBS合并SIADH的发病机制尚未被完全阐明，据猜想是由于渗透重置和增强了肾小管对抗利尿激素的敏感性所致。
Treatment of small fiber GBS is the same as other forms of GBS, and includes immunomodulatory therapy with IVIg or plasma exchange. Symptomatic treatment of neuropathic pain can be considered with GABA agonists, opioids, and nonsteroidal anti- inflammatory agents.
小纤维型GBS的治疗与其他形式的GBS相同，包括静注免疫球蛋白的免疫调节治疗及血浆置换。神经性疼痛的对症治疗可以考虑GABA受体激动剂、阿片类药物和非甾体抗炎药。
This case illustrates a patient with an acute small fiber neuropathy and highlights the role of blood tests, neurophysiology, lumbar puncture, and skin biopsy in its diagnosis. The most likely etiology is sensory GBS. According to the proposed classification for sensory GBS, our patient has an acute sensory small fiber neuropathy ganglionopathy.
此文描述了一例急性小纤维神经病的患者，突出了血液检查、神经生理学、腰椎穿刺及皮肤活检在诊断中的重要作用。最可能的病因是感觉型GBS。根据感觉型GBS推荐的分类方法，此例患者考虑为急性感觉型小纤维神经节神经病。
（全文终）
古诗文欣赏
去年今日此门中，人面桃花相映红，
人面不知何处去，桃花依旧笑春风。
Same day yester year， Same blossoming cherry trees
Where goes my dear ，Solitude blooms in gentle breeze
编辑：李会琪
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